Pathogen recognition by the innate immune system relies on a limited number of fixed germline-encoded receptors which have evolved to identify conserved microbial structures both not shared by the host and essential for their survival, the so-called pathogen-associated molecular patterns (PAMPs) (1, 2). Examples of PAMPs are lipopolysaccharide (LPS) from Gram-negative bacteria, lipoteichoic acid (LTA) and peptidoglycan (PGN) from Gram-positive bacteria, lipoarabinomannan from mycobacteria, and β-glucans and mannan from fungi. Several structurally and functionally diverse classes of pattern-recognition receptors (PRRs) exist which induce various host defense pathways. Protein domains involved in pattern recognition include, among others, the C-type lectin domain from Dendritic Cell (DC) lectins, the leucine-rich repeat (LRR) from Toll-like receptors (TLR), and the scavenger receptor cysteine-rich (SRCR) (2). The later was first described upon cloning of mouse type I class A macrophage scavenger receptor (SR-AI) (3). Sequence comparison with several other proteins, such as the sea urchin speract receptor, human and mouse CD5, and complement factor I revealed the existence of a conserved, 100 amino acid-long motif characteristic of a new superfamily of protein receptors, named the SRCR-SF. This family is currently composed of more than 30 different cell-surface and/or secreted proteins with representatives in most animal phyla, from low invertebrates to mammals (4). The members of the SRCR-SF are divided into two groups: group A members contain SRCR domains composed of 6 cysteines and encoded by two exons, whereas those of group B contain 8 cysteines and are encoded by a single exon. Recent structural data indicate, however, that both group A and B SRCR domains share a similar scaffold (a central core formed by two antiparallel β-sheets and one α-helix), the main differences being observed at the connecting loops (5). This situation recalls that of other few successful protein modules of the immune system from which evolution has settled and built a myriad of different proteins (e.g., immunoglobulin domain). The versatility of these conserved domains lies in the fact that key residues stabilizing the domain structure are conserved throughout evolution while other can evolve freely (especially those at the external loops) giving rise to great functional diversity (6). Accordingly, in spite of their high degree of structural and phylogenetic conservation there is not a unifying function reported for the SRCR domains. Some of them have been involved in protein-protein interactions being the most well studied examples of it the interaction of the CD6 lymphocyte receptor with CD166/ALCAM, a transmembrane adhesion molecule belonging to the Ig superfamily (7, 8), and that of the CD163/M130 macrophage receptor with the haemoglobin-haptoglobin complex (9). A few members of both group A (i.e., SR-AI/II, MARCO, and SCARA5) and B (i.e., DMBT1, Spα, and CD6) SRCR-SF are also known to interact with PAMPs present on bacterial surfaces, such as LPS, LTA and PGN. Although these interactions were initially mapped outside the SRCR domain (10), recent evidence demonstrate the direct involvement of SRCR domains on it (11-14). Therefore, whether pathogen scavenging is a general property shared by all members of the SRCR-SF or only by a selected group of its members remains to be analyzed.
The transmembrane type I receptors CD5 and CD6 are two lymphoid group B members of the SRCR-SF. Both share important similarities at structural and functional level and are encoded by contiguous genes in the same chromosome region thought to derive from duplication of a common ancestral gene (15, 16). CD5 and CD6 are expressed on thymocytes from early stages of their development, on mature peripheral T cells, and on B1a cells, a small subset of mature B cells responsible for the production of polyreactive natural antibodies and which is expanded in certain autoimmune diseases and in B-cell chronic lymphocytic leukemias (17). The extracellular regions of both CD5 and CD6 are exclusively composed of three consecutive group B SRCR domains, which show extensive amino acid sequence identity (5). The main differences between CD5 and CD6 are found at their large cytoplasmic regions, both of which are devoid of intrinsic catalytic activity but contain several structural motifs compatible with a function in signal transduction (18, 19). In that regard, CD5 and CD6 are physically associated to the antigen-specific complex present on T (TCR) and B (BCR) cells (20, 21) and co-localize with it at the centre of the immunological synapse (21, 22). Therefore, CD5 and CD6 are well positioned to either positively or negatively modulate the activation and differentiation signals generated by the antigen-specific receptor (22-26) through still incompletely understood and complex signalling pathways (23, 27-29). This is likely achieved through engagement of the CD5 and CD6 ectodomains by different cell surface counter-receptors. While, it is well established that CD6 binds to CD166/ALCAM (30), a bona fide CD5 ligand is still due (31-35). Interestingly, CD5 and CD6 appear to differ at residues critical for binding to CD166/ALCAM (36).
In a previous study, the bacterial binding capabilities of the CD5 and CD6 ectodomains, both known to also exist as soluble forms circulating in serum (37, 38) were explored. The reported data indicated that both soluble and membrane forms of CD6, but not of CD5, bind to the surface of Gram-negative and Gram-positive bacteria through recognition of specific PAMPs (namely, LPS and LTA, respectively) (39).
Other studies have shown that those cells, either T cells or B cells, expressing CD5 receptor in the surface have the capability of recognize and affect, to a greater or lesser extent, the normal development of C. neoformans and C. albicans (48, 49).
However, the mechanism by which this receptor recognizes or has the affinity for fungal cells has not been described nor suggested.
Now, the authors of the present invention have extended these studies to the analysis of the recognition and binding properties of CD5 and CD6 to fungal structures and have shown that, compared to CD6, the CD5 ectodomain is well suited for the recognition of conserved components on fungal cell surfaces, showing for the first time that said extracellular region isolated from the CD5 receptor can provide prophylaxis in vivo itself against an general fungal infection, not only against C. neoformans y C. albicans. 
The authors have shown that fungal cells are specifically recognized, bound and aggregated by soluble forms of the CD5 ectodomain. This is done through the recognition of β-glucans, a conserved structural component of fungal cell walls, by the soluble CD5 ectodomain.
Furthermore, the authors of the present invention have surprisingly found that soluble CD5 ectodomains have a protective effect in the mouse model of zymosan-induced septic shock-like syndrome.
These results support the therapeutic utility of the infusion of soluble human CD5 ectodomain for the treatment of septic shock syndrome or other inflammatory processes of fungal origin.